Acupuncture, 1–4
placebo response in, 4–5, 146–147
Ader, Robert, 51
Adherence, medication, 121
Advertising and marketing of patent medicines, 30–32
AKL-T01, 161
ALKS-5461, 123
Allergic reactions, 100
Altman, Jack, 50
Alzheimer’s disease, 111–113
American Medical Association (AMA), 25
efforts to halt quackery, 31–32
Seal of Acceptance, 31
American Psychiatric Association, 25
American Society of Clinical Psychopharmacology, 119
Amygdala, 70
Anterior cingulate cortex (ACC), 71, 75, 91
Antihypertensive drugs, 134
Apps, 161–162
Arthroscopic surgery, 133–134, 136
Associative learning, 48, 49–53, 68, 72–73
Atorvastatin (Lipitor), 94
Back door, placebos as, 11–13, 87, 162–165
Bailly, Jean-Sylvain, 20
Baquets, 19–20
Beauchamp, Thomas, 37
Beecher, Henry, 37–39, 127, 130, 136, 137, 147
Bell Curve, The, 49–50
Belmont Report of 1978, 37
Benedetti, Fabrizio, 40
Beta-blockers, 98–99
Big five personality traits, 140
Bingel, Ulrike, 56–57
Biogen, 112–113
Biohaven Pharmaceuticals, 113
Brain, the
endogenous and exogenous opioids, 71–72
neurons and neurotransmitters in, 69–70
nocebo effect and, 91–92
during pain, 68–71
pain matrix in, 70–71
Parkinson’s disease and major depression and, 84–86
placebo analgesia and, 72–76
placebo effects in, 87
in placebo responders, 141–142
predictive coding toward model of precision and placebo analgesia, 81–84
top-down processing and placebo effects, 79–80
ventromedial prefrontal cortex (vmPFC), 76–79
Buchel, Christian, 80
Buske-Kirschbaum, Angelika, 52
Cabot, Richard, 33
Can Shoulder Arthroscopy Work? (CSAW) clinical trial, 128
Cardiovascular disease and statins. See Statins
Catechol-O-methyltransferase (COMT), 145–146, 148–150
Centers for Medicare & Medicaid Services, 113
Charlatans, 26–30
Chaucer, Geoffrey, 6
Childress, James, 37
Cipriani, Andrea, 119
Classical conditioning, 49, 52
Clinical trials, 10–11
Alzheimer’s disease drugs, 111–113
current state of placebos in, 124–126
double-blinded, 109–110
early use of placebos as controls in, 34–37, 124
ethical practices for, 36–37, 40–41
failure of drugs in, 110, 120, 124–126, 158
Hawthorne effect in, 108–109
Haygarth’s early, 21–24
lead molecule in, 107–108
minimizing placebo responses in, 120–123
natural history in, 109
n-of-1 trial, 96–97
open-label placebo (OLP), 159–160
on Parkinson’s disease and major depression, 84–86
patient heterogeneity in, 121
placebos as controls in, 34–37, 108–110
Coblenz, J. W., 32
Codeine, 71
Cohen, Nicholas, 51
Collier’s, 32
Complementary and alternative medicines, 4
Computational tools for predicting placebo responders, 142–145
Conditioning. See Expectation and conditioning
Cortexyme, 113
nocebos and, 104–105
placebos and, 156–157
Critical Path Institute, 111
Cyclophosphamide, 51
Declaration of Helsinki, 36
Depression, placebo response in clinical trials on, 86, 114–119
Digiceuticals, 11
Digital health technologies, 161–162
Dose-extension studies, 52
Double-blinded studies, 109–110
Drug development, 107–108
Dubois, Eugene, 35–36
Elixir Sulfanilamide, 34
Ellis, Thomas, 22
Ellsworth, Oliver, 17
Eltroxin, 103–104
Endo, Akira, 92–94
Endorphin, 71
Enkephalin, 71
Epinephrine, 52
Erectile dysfunction (ED), 98–99
Ethical issues
in clinical research, 36–37, 41
in predicting placebo responders, 153–154
sham surgery, 132–133
Expectation and conditioning, 9–10, 47–48
associative learning in, 48, 49–53, 68, 72–73
cost, branding and cost-related cues and, 62–65
differences between, 53
immune function, 50–52
labeling effects on, 61–62, 63
mirror cure for phantom limb pain, 53–55
neurological activity during, 68
pain induced by, 55–56
as shaped by past experience and malleable, 56–62
Failures of drugs in clinical trial, 110, 120, 124–126, 158
Fava, Maurizio, 122
Federal Food, Drug, and Cosmetic Act of 1938, 34
Fields, Howard, 39
Fleming, Alexander, 92
Fluoxetine (Prozac), 114
Food and Drug Administration (FDA), 34, 110, 113, 116, 117, 119, 123
Franklin, Benjamin, 20, 21–24, 41, 155
Functional magnetic resonance imaging (fMRI), 69, 142
Garbage gene, 145
Gene-drug interactions, 147–151
Genetics and placebo response, 145–151
Gilbert, Susan, 81
GlaxoSmithKline, 103–104
Gold, Harry, 35–36
Great American Fraud, The, 30, 32
Guillotin, Joseph-Ignace, 20
Hahnemann, Samuel, 25–26
Hamilton depression rating scale (HDRS), 118–119
Hawthorne effect, 108–109
Haygarth, John, 15–16, 18–19, 21–24, 41, 46, 155
Helmholtz, Hermann von, 81, 84
Heroin, 71
Herrnstein, Richard J., 49–50
Heterogeneity, patient, 121
Homeopathy, 25–26
Howe, Lauren, 100
Hydrocodone, 71
Hydrotherapy, 26
Hyperalgesia, 92
Hypertension, 134
Hypnosis, 24–25
Hypnotists, 24
Hypothalamus, 70
Immune function, 50–52
Integrative medicine, 4
early, 24–26
Journal of the American Medical Association, 31, 38
Kam-Hansen, Slavenka, 61
Kaptchuk, Ted, 40
Kennedy, Walter, 91
Keytruda, 124
Khan, Arif, 115–116
Kirsch, Irving, 40, 115, 117–119
Lancet Digital Heatlh, 161
Lavosier, Antoine, 20
Lee, Arthur, 21
Levine, Jon, 39
Levothyroxine, 102–103
Lithium chloride, 51
Louis XVI, King, 20
Lovastatin, 94
Mammary artery ligation, 128–131
Marie Antoinette, 20
Marshall, John, 17
Mesmer, Franz Anton, 18–19, 25, 41, 155
Mesmerists, 24
Mirror visual feedback (MVF), 53–55
Moseley, J. Bruce, 133
Mrs. Lydia E. Pinkham’s Vegetable Compound, 28–30
Naloxone (Narcan), 39, 50, 74, 80
National Institute for Health and Care Excellence (NICE), 118
National Institutes of Health, 25
Natural history, 109
Neuroimaging. See Brain, the
Neurons, 69–70
Neurotransmitters, 69–70
New England Journal of Medicine, 133
“New Surgery for Ailing Hearts,” 129
Nocebo effect, 9–10
beta-blockers and erectile dysfunction (ED), 98–99
brain and, 91–92
in the clinic, 99–100
death as ultimate, 90
defined, 91
hyperalgesia, 92
in popular culture, 102–105
and racism in the clinical encounter, 101–102
statin denialism and, 95–96
superstition and, 89
Nociceptors, 70–71
N-of-1 clinical trials, 96–97
Nostrums, 7, 24, 26–27, 30–31, 32
Nucleotides, 145–146
Nuremberg Code of 1947, 36
Of the Imagination, as a Cause and as a Cure of Disorders of the Body; Exemplified by Fictitious Tractors and Epidemical Convulsions, 22, 155
Open-label placebos (OLP), 158–160
Opioids
opioid antagonists, 39
opioid receptors, 69–70
opioids and pain, 39, 70, 71–72
OxyContin, 71
radioactive carfentanil, 74
Optimism, 140
Pacemaker trial, 130–131
Pain. See also Opioids
brain during, 68–71
induced by expectations, 55–56
nociceptors and, 70–71
Palliative placebos, 18
Paluridine, 124
Parkinson’s disease, 84–85, 131
Paroxetine (Paxil), 114
Pasteurization, 24
Patent/proprietary medicine, 7, 18, 26–30
advertising and marketing of, 30–32
regulatory affairs and, 33–34
Pavlov, Ivan Petrovich, 49, 53
Penicillin, 92
“Perception of an Object Costs,” 67
Perkin’s tractors, 16–18, 19, 21–24
Personality trait indexes, 138–139
big five traits and, 140
inward versus outward traits in, 141
Pessimism, 140
Phantom limb pain, 53–55
Pihl, Robert, 50
Placebo analgesia
brain activity during, 74–76
clinical trials on Parkinson’s disease and major depression and, 84–86
neuroimaging studies of, 72–73
predictive coding toward model of precision and, 81–84
Placebo effect, 4–5, 7–8, 155–156
expectation and conditioning promoting, 9–10, 48–49
in surgery (See Surgery)
theories of expectation and conditioning in, 40
top-down processing and, 79–80
Placebome, 151
Placebo run-in, 122
Placebos
as back door to health, 11–13, 87, 162–165
in clinical trials (see Clinical trials)
digital health technologies and, 161–162
experimentation on, 1960s-1970s, 39–41
Henry Beecher’s research on, 37–39
open-label, 158–160
origin of term, 6
palliative, 18
regulation of, 33–34
responders to (see Responders, placebo)
in sham acupuncture, 4
timeline of development of, 42–45
in time of COVID-19, 156–157
Popular culture, nocebos in, 102–105
Positron emission tomography (PET), 69, 74, 75
“Powerful Placebo, The,” 137, 147
Precision, 81–84
Predictive coding, 81–84
Prefrontal cortex (PFC), 91, 145–146
Program in Placebo Studies (PiPS), 40–41
Psychological markers of placebo responders, 139–141
Pure Food and Drugs Act of 1906, 33
AMA efforts to halt, 31–32
marketing and, 30–32
Racism and nocebo in clinical encounters, 101–102
Ramachandran, Vilayanur, 53
Ratcliff, J. D., 128–129
Receptors, neuron, 69–70
Regulation of medicines, 33–34
Responders, placebo
ethical concerns in predicting, 153–154
genetics and, 145–151
neuroimaging of, 141–142
personality type of, 138–139
psychological markers of, 139–141
studies and predictions of, 137–138
using computational tools to predict, 142–145
Rizatriptan (Maxalt), 61–62, 63
Rostral ventromedial medulla (RVM), 76
Saccharin, 51–52
Sapirstein, Guy, 115
Schoenfeld, David, 122
Scopolamine, 49–50
Sequential parallel comparison design (SPCD), 122–123
Sertraline (Zoloft), 114
Sham acupuncture, 4
Shamans, 8–9
Sham surgery, 128–131
ethical issues in, 132–133
studies comparing surgery to, 133–134
Sildenafil, 98
Smartphones, 161–162
Society for Interdisciplinary Placebo Studies (SIPS), 40–41
Somatosensory cortex, 71
Standardized mean difference (SMD), 117–118
Statins, 10
denialism and nocebo effects toward, 95–96
effects on cardiovascular disease, 92–95
n-of-1 study on side effects of, 96–97
Rosuvastatin (Crestor), 94
Stone, Marc, 119
Streptomycin, 124
Superstition, 89–90
arthroscopic debridement and lavage, 133–134
compared to sham surgery, 133–134
mammary artery ligation as early casualty of sham controls in, 128–131
renal denervation, 134
“Surgery as Placebo,” 127
Thorazine, 50
Thyroid hormone replacement drugs, 103–104
Top-down processing and placebo effects, 79–80
TransCelerate, 111
“Truth and Falsehood in Medicine,” 33
Turner, Erick, 117–119
Vaccines, 24
early investigations into smallpox, 18, 21
Vasopressin, 70
Vedantam, Shenkar, 107
Ventromedial prefrontal cortex (vmPFC), 76–79, 91, 163
Virtual reality, 161
Wager, Tor, 76
Washington, George, 17
Washington Post, 107
Wonder, Stevie, 89
Xanthines, 35
XPILL, 160
ZEEBO, 160